Histone deacetylases (HDACs) have been extensively studied for their roles in transcriptional regulation and chromatin remodeling. HDACs are divided into four classes, according to sequence homology and domain organization (Dokmanovic et al. (2007) Mol. Cancer Res. 5: 981-9). Class I includes, for example, HDACs 1, 2, 3, and 8; class II includes, for example, HDACs 4, 5, 6, 7a, and 10; class III includes, for example, sirtuins; and class IV includes, for example, HDAC11.
HDACs have also drawn research interest because inhibitors of these enzymes display anti-tumor activities (reviewed in Drummond et al. (2005) Annu Rev Pharmacol Toxicol 45: 495-528). Certain HDAC inhibitors (HDACI) are at various stages of clinical trials for cancer patients, and at least one (SAHA/vorinostat) has been approved for clinical use (Gallinari et al. (2007) Cell Res 17: 195-211). Despite the potent activity of these compounds, the question of how HDAC inhibitors achieve their anti-tumor effect remains poorly understood. The well-established role for HDACs in histone acetylation and gene transcription has led to a general assumption that HDAC inhibitors achieve their therapeutic effects by affecting transcriptional programs important for proliferation and apoptosis.
The recent characterization of cytoplasmically-localized HDAC6 reveals that this class of enzymes has functions independent of histones and chromatin. (Bali et al. (2005) Biol Chem 280: 26729-26734; Boyault et al. (2007) Genes Dev 21: 2172-2181; Hubbert et al. (2002) Nature 417: 455-458; Kawaguchi et al. (2003) Cell 115: 727-738; Kovacs et al. (2005) Mol Cell 18: 601-607; Kwon et al. (2007) Genes Dev 21: 3381-3394). Supporting this view, a mass spectrometry-based proteomic analysis has identified a large number of acetylated proteins that have no apparent links to chromatin or gene transcription. (Kim et al. (2006) Mol Cell 23: 607-618) Among these non-nuclear acetylated proteins, some are mitochondrially localized, raising the possibility that certain mitochondrial functions may be regulated by reversible acetylation.
In addition to implying additional regulatory functions for HDACs outside the nucleus, these findings also raise the question as to whether non-genomic processes may also be affected by HDACI therapeutics.